The genetic abnormalities defined for AML in WHO 2022 and the recurrent genetic abnormalities in ICC 2022 are similar to those listed by WHO in 2017, with small differences, mentioned in Table 1.

In the case of CEBPA gene mutations (CCAAT enhan­cer binding protein A gene), WHO 2022 involves biallelic mutations (biCEBPA) and single mutations located in the basic leucine zipper region of the smbZIP-CEBPA gene, while ICC 2022 includes only in-frame bZIP; recent studies consider that a favorable prognosis is associated with patients with CEBPA in-frame bZIP mutations, regardless of their appearance as biallelic or monoallelic mutations^(7,8-10).

The entity AML with RUNX1 mutation from WHO 2017 was reclassified into subtypes in both classifications (WHO 2022 and ICC 2022), as follows:

• 74.4% as AML with myelodysplasia-related changes (AML-MR)
• 22% as AML with differentiation-related changes (AML-DD)
• 2.4% as AML with mutated CEBPA (AML-CEBPA)
• 1.2% as AML with MECOM rearrangements (AML-MECOM).

The classification of high-grade myelodysplastic syndromes (high-grade MDS) represents another point of divergence between the two classification systems of acute myeloid leukemias.

A series of updates was brought to the AML entity with changes related to myelodysplasia (AML-MR; myelodysplasia-related changes), which in 2022 was renamed as AML-MR myelodysplasia related, and it was divided into two subcategories by the ICC: acute myeloid leukemia acute with genetic mutations related to myelodysplasia (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1 or ZRSR2) and acute myeloid leukemia with cytogenetic abnormalities related to myelodysplasia. Morphologically, the required percentage of described blasts is ≥20%. A history of myelodysplastic syndrome or myeloproliferative neoplasm represents a descriptive condition in the diagnosis, but it does not represent a classification criterion. Both the new WHO classification and the ICC guide emphasize the genetic lesions associated with myelodysplasia in AML, as part of the ontogenetic process. However, the framing of these genetic anomalies cannot be superimposed in these two systems, leading to discrepancies in the clinical management of patients.

Cytogenetic and molecular abnormalities in acute myeloid leukemia related to myelodysplasia (AML-MR; myelodysplasia related; WHO 2017/2022 and ICC 2022)

An important category, mentioned by ICC, is given by acute myeloid leukemia with mutant TP53. To support this diagnosis, it is necessary that the percentage of blasts be at least 20% and that there is any TP53 somatic mutation at the level of a varied allelic fraction of more than 10%; if the percentage of blasts was between 10% and 19%, then it would be classified as SMD/LAM with mutated TP53. The prognosis of these patients is unfavorable, presenting numerous anomalies, sometimes being associated with a complex karyotype^(11-15). Due to the frequent correlation of pure erythroid leukemia with TP53, in ICC these cases will be classified as acute myeloid leukemia with mutant TP53.

In the case of patients with a percentage between 10% and 19% blasts in the periphery and/or bone marrow, a new category was introduced by ICC: myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), replacing MDS with excess blasts, grade 2 (WHO 2017), thus creating the opportunity for patients to participate in clinical trials (MDS or AML). WHO 2022 continues to classify these patients as having myelodysplastic syndrome with increased number of blasts grade 2 (MDS-IB2; increased blasts 2), name changed to MDS with excess blasts, a measure taken to avoid overtreatment, although WHO mentions that MDS-IB2 can be considered AML for therapeutic purposes, if it has a clinical indication.

It has been shown that the incidence of AML cases in patients with neoplastic history is increasing, currently representing 10-15% of all newly diagnosed AML⁽¹⁶⁾. It is considered that these neoplasms are the direct consequence of mutational events induced by cytotoxic therapy and/or the selection of clones resistant to chemotherapy^(17-19). In 2022, WHO divided myeloid neoplasms secondary to exposure to cytotoxic therapy or germline predisposition in the major category of secondary myeloid neoplasia with three subcategories: post-cytotoxic therapy myeloid neoplasia (previously called therapy-related AML), MN-pCT – myeloid neoplasms associated with germline predisposition, and myeloid proliferation associated with Down syndrome.

According to the ELN 2022 classification, the FLT3-ITD mutation is part of the intermediate risk group, regardless of the allelic ratio or the concomitant presence of NPM1. AML with gene mutations related to myelodys­plasia is now included in the unfavorable risk group.

ELN classification of the genetic risk group at diagnosis in 2022

Favorable:

• t(8;21)(q22;q22.1)/RUNX1::RUNX1T1.
• inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11.
• NPM1 mutant without FLT3-ITD.
• bZIP in-frame mutated CEBPA.

Intermediate:

• NPM1 mutant with FLT3-ITD.
• Wild-type NPM1 with FLT3-ITD (without genetic lesions with adverse risk).
• t(9;11)(p21.3;q23.3)/MLLT3::KMT2A.
• Cytogenetic and/or molecular anomalies not classified as favorable or adverse.

Unfavorable:

• t(6;9)(p23.3;q34.1)/DEK::NUP214.
• t(v;11q23.3)/KMT2A – rearranged#.
• t(9;22)(q34.1;q11.2)/BCR::ABL1.
• t(8;16)(p11.2;p13.3)/KAT6A::CREBBP.
• inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2, MECOM(EVI1).
• t(3q26.2;v)/MECOM(EVI1) – rearranged.
• −5 or del(5q); −7; −17/abn(17p).
• Complex karyotype, monosomal karyotype.
• ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2*mutant.
• TP53 mutant (VAF at least 10%).

Monosomal karyotype = the presence of a single monosomy (except loss of X or Y chromosomes) in association with at least one more monosomy or another chromosomal abnormality (except core-binding factor).

Complex karyotype = the presence of three or more chromosomal anomalies, unrelated in the absence of other recurrent genetic anomalies, define a class, exclude hyperploid karyotypes with three or more trisomies, without structural anomalies.

* if they are associated with mutations in the cate­gory of those with a favorable prognosis, they are no longer factors of an unfavorable prognosis;

# it is frequently associated with the complex or monosomal karyotype.

The correct and complete diagnosis of AML is important for obtaining complete remission, and with the help of targeted therapy (anti-FLT3, IDH1, IDH2, BCL2) or menin inhibitors (KMT2 rearrangement, NPM1 mutation)^(20-23). At the same time, based on the cytogenetic and molecular genetic characteristics at diagnosis and the response to treatment, the indication for hemato­poietic cell transplantation, the only method of curative therapy will be decided. Cytogenetic evaluation of patients with AML at the time of diagnosis is important in order to obtain complete remission and maintain it, thus ensuring an increased quality of life for the patient.

The development and implementation of a unified classification system require a critical and permanent review of the current literature, as well as the integration of new investigations available in the field of acute myeloproliferations. The initiative is shaped and supported by multiple international consortia whose area of research specifically targets MDS and AMLs, seeking a patient-centered approach to care and better clinical integration of cohort data from the literature. An ideal model for a classification system will require continuous involvement and harmonization of the existing data.  

Corresponding author: Meilin Omer E-mail: meilin_26@yahoo.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.